Vasoreactivity testing in Pulmonary Hypertension as a guide to treatment and responsiveness to calcium channel blockers

1. P R E S E N T E D B Y :
D R . H I M A N S H U R A N A

2. Introduction
 Pulmonary hypertension is defined by a mPAP of 2o mm
Hg or more at rest, as measured by right heart
catheterization
 The normal mean pulmonary artery pressure at rest is
14±3.3 mmHg with an upper limit of normal of
approximately 20 mmHg
 This value is independent of sex and ethnicity, and is only
slightly influenced by age and posture.
Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary
hypertension. Eur Respir J 2019; 53: 1801913 [https://doi.org/ 10.1183/13993003.01913-2018]. The 6th WORLD SYMPOSIUM
ON PULMONARY HYPERTENSION

3. Introduction
 PVR ⩾3 WU in the definition of all forms of pre-capillary
PH.
 Pre-capillary PH is best defined by the concomitant
presence of mPAP >20 mmHg, PAWP ⩽15 mmHg and PVR
⩾3 WU.
 PAH – pulmonary artery wedge pressure ≤15 mmHg and a
PVR >3 Wood units in the absence of other causes of
precapillary PH such as PH due to lung diseases, CTEPH or
other rare diseases

4. Hemodynamic definitions of PH
Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary
hypertension. Eur Respir J 2019; 53: 1801913 [https://doi.org/ 10.1183/13993003.01913-2018]. The 6th WORLD SYMPOSIUM
ON PULMONARY HYPERTENSION

5. Classification

6. Classification

7.  Group 5 (PH with unclear and/or multifactorial
mechanisms) was simplified with
1) the removal of splenectomy and thyroid disorders,
and
2) the classification of LAM-associated PH together
with other parenchymal lung diseases in group 3.

8. Pathophysiology

9. Calcium channel blockers
High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in
pulmonary arterial pressure and regression of right ventricular hypertrophy. Rich S, Brundage BH Circulation. 1987 Jul;

10. Vasoreactivity testing
Why
required?

11. Calcium channel blockers

13. Vasodilator testing
 It should be performed at the time of RHC
 Done to assess the CCB responsiveness in PAH patients
 Inhaled NO at 10–20 ppm is the standard of care for
vasoreactivity testing
 i.v. epoprostenol, i.v. adenosine or inhaled iloprost can be
used as alternatives
 The use of CCBs, O2, PDE- 5 inhibitors or other
vasodilators for acute vasoreactivity testing is discouraged

14. Indications
ESC/ERS- 2018
All patients with IPAH, HPAH and PAH associated
with drugs

15. Other indications for testing
 Complicated congenital heart disease with severe PAH to
determine the next best step in management
 Prior to Fontan surgery or one of its modifications, with
elevated PVR
 Heart transplantation candidates to assess the need for
concomitant lung transplantation
 High cost of PDE 5 and endothelin receptor antagonists

16. Contraindications
IPAH patients with overt RVF or hemodynamic
instability should not undergo acute vasodilator
testing

17. University of Florida pulmonary vasodilator
testing protocol
1. Confirm indication, review medical records and perform brief medical history
2. Consent
3. ECG, blood pressure and peripheral oximetry monitors
4. USG guided right internal jugular vein (preferably) cannulation
5. Place a pulmonary arterial catheter by fluoroscopic guidance
6. Obtain resting right heart, pulmonary and PAOP in supine position and
breathing room air or oxygen to maintain above 90%
7. If PAOP measurement is not reliable obtain LVEDP

18.  8. Measure CO by thermodilution (severe TR, Fick methodology is
recomended) Calculate cardiac index and PVR
 9. Withdraw blood from distal port of pulmonary catheter for mixed venous
O2. If needed obtain oxygen saturations from SVC, IVC and RV
 10. If patient meets criteria for PAH proceed with NO challenge
 11. Administer NO 20 ppm on 100% O2 for 5 min through a face mask
 12. Repeat measurements of PAP and CO
 13. Define if patient has a positive pulmonary vasodilator test
 14. If no need to repeat measurements, end of study
University of Florida pulmonary vasodilator
testing protocol

19. Sitbon criteria 2005
Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension.Sitbon O,
Humbert M, Jaïs X, Ioos V, Hamid AM, Provencher S, Garcia G, Parent F, Hervé P, Simonneau G Circulation.
2005 Jun 14; 111(23):3105-11.
A positive acute response is defined as a
reduction of Mean PAP ≥10 mmHg to
reach an absolute value of mean PAP ≤40
mmHg with an increased or unchanged CO

20. Other criteria
 Barst criteria, 1986: decrease in mPAP of ≥20%,
unchanged or increased cardiac index, and decreased
or unchanged PVR to SVR ratio (PVR/SVR)
 Rich criteria, 1992: decrease in mPAP and PVR of
≥20%
Rich S, D'Alonzo GE, Dantzker DR, Levy PS. Magnitude and implications of spontaneous hemodynamic
variability in primary pulmonary hypertension. Am J Cardiol 1985; 55(1):159-63

21. Positive response
 A positive test is not synonymous with benefit from CCB
therapy, but is required before starting treatment
 Less than 10% of IPAH patients have an acute response and
only half of these patients go on to have a long-term
response to CCBs

22. When to stop testing ?
 Target response achieved
 SBP drop by ≥ 30% or < 85 mmHg
 HR increase by 40% or greater than 100/min
 HR drop to less than 60 with symptomatic hypotension
 Intolerable side effects such as headache, lightheadedness,
nausea, vomiting
 Maximum dose of vasodilator agent given

23. Characteristics of vasodilators
 Short acting
 Easy to administer
 Safe with few systemic effects
 Inexpensive
 Available

24. Inhaled NO
 The DOC for vasodilator testing
 An initial dose of 10 ppm is given as inhaled gas via face mask
 Increased in a step wise fashion every 5 – 10 minutes to a
maximum of 80 ppm
 iNO vasodilates the pulmonary circulation selectively
 It preferably acts on well-ventilated airways, decreasing
pulmonary shunt
 Very short half-life of three minutes

25. Model for NO via face mask

26. INOmax DSIR
®

27. Inhaled NO
Disadvantages
 Dose for vasodilator testing is not standardized
 The cost of using iNO to test pulmonary vasoreactivity is
US$50.00 since it is used for a short time during the
procedure
 However, a cylinder and a monitor need to be available,
and this makes the procedure more costly in facilities where
it is rarely used
Adverse effects
 Rebound PH
 Pulmonary edema in pulmonary venous hypertension
(PVH)

28. Epoprostenol
 Alternative to iNO in both ESC and ACC guidelines
 An initial dose of 2 ng/kg/min given IV & can be increased in astep wise
fashion every 10 – 15 min to a max of 12 ng/kg/min
 Shown similar pulmonary vasodilator effects compared to iNO life of up
to 6 minutes
 Expensive, unstable at room temperature
 Adverse reactions like flushing, headache and
hypotension due to systemic vasodilator effects

29. Adenosine
 Very short half-life of five to ten seconds
 An initial dose of 50 mcg/kg/min is given IV & can be
increased in a step wise fashion every 2 min to a maximum
of 500 mcg/kg/min
 Relatively cheap
 Severe adverse effects due to systemic vasodilator effects
like palpitations, bronchospasm, hypotension, bradycardia
and atrioventricular block have been reported

32. Inhaled Iloprost
 Prostaglandin analog & more potent than iNO
 Intrapulmonary selectivity and decreases
systemic side effects as well as ventilation-
perfusion mismatch
 It directly acts on the adventitial side of the
pulmonary artery wall
 Ventavis , delivery system for iloprost not
available in India

33. Inhaled Iloprost
 An initial dose of 2.5 mcg/kg/min is given IV and this can
be increased in a step wise fashion every 30 minutes to a
maximum of 5 mcg/kg/min
 Iloprost has a long half-life of 30 minutes and this can
result in a longer duration of testing time
 Side effects include headache, flushing, jaw pain, dizziness
and hypotension

34. Oral Sildenafil
 The European guidelines report that oral sildenafil
has unproven predictive value and significant
systemic vasodilator effects
 Intravenous preparation not available

35. Pure oxygen
 Congenital heart disease
 Pure oxygen should not be the drug of choice in other PAH
 Available in all facilities, being easily administered, and having
almost no side effects
 When pure oxygen is used to test pulmonary vasoreactivity in
cases of congenital heart disease, the dissolved oxygen should be
included in the calculations of pulmonary blood flow (Qp) and
systemic blood flow (Qs)
 False-positive results

36. Calcium channel blockers
 CCBs should not be used for vasodilator testing due to
complications
 CCBs were the first agents that were employed in the early
days of vasodilator testing
 However, life-threatening hemodynamic compromise has
often been documented in nifedipine and verapamil testing
 Possibilities include decreased myocardial contractility,
hypotension and activation of the renin-angiotensin-
aldosterone system

37. Intravenous Nicardipine

42. Pediatric pulmonary hypertension
 To assess prognosis and indication for specific PH therapy-
Class I
 To assess operability of APAH-CHD- Class I
 Vasoreactivity testing should be performed using nitric
oxide as vasodilator- class I
 The use of CCBs, intravenous epoprostenol or intravenous
adenosine in AVT is not recommended in children, and
may cause harm – class III

43. Pediatric IPAH/HPAH
Modified BARST criteria
 >20% fall in mean PAP and PVRi /SVRi ratio without a decrease in
cardiac output
 In the presence of a positive AVR, a fall of the ratio of PVRi/SVRi below
0.4 due to the AVT might be an indication for CCBs
 A positive AVR can fade over time, and this may have consequences on
the PH-specific pharmacotherapy
 Repeat AVT annually unless a highly significant clinical and
haemodynamic improvement could be achieved
Apitz C, et al. Heart 2016;102:ii23–ii29.

44. APAH-CHD and shunt
 Use of pure oxygen as an agent to test AVR should be avoided, if other
pulmonary vasodilators are available
 Positive response to AVT in PAH associated with a shunt defect (Qp:Qs
>1.5:1; APAH-CHD-shunt) for children should be considered as a >20% fall
in PVRi and PVRi/SVRi with respective final values <6 indexed Wood units
(iWU) and <0.3
 In functional single ventricle physiology mPAP of >15 mm Hg may be
associated with early and late mortalities after the Fontan operation
 In single ventricle physiology after Fontan PHT is present, when dTPG is
>6 mm Hg or PVR >3 iWU, even if the mPAP is <25 mm Hg
 In Fontan patients, a PVR of less than 2.5 iWU belongs to criteria of low
risk, resistance values between 2.5 iWU and 4 iWU have an intermediate
risk, PVR above 4 iWU usually is considered unsuitable for a Fontan
circulation
Apitz C, et al. Heart 2016;102:ii23–ii29. doi:10.1136/heartjnl-2014-307340

45. Pulmonary Hypertension due to left heart disease
– Group 2
 The role, protocol and significance of vasodilator testing
in PH due to LSHD is uncertain, except to identify
patients at high risk for acute post-operative RVF
 Inotropes, vasodilators, prostanoids, NO, and PDE-5
inhibitors have been used for testing the pulmonary
circulation responsiveness

46. Pulmonary Hypertension due to left heart disease
– Group 2
 Reactivity testing with nitroprusside or milrinone
 If PAWP decreases and PVR< 4 with an increase in CO- LSHD-
directed therapy including diuretics, nitrates and effective blood
pressure control is beneficial
 If no response to nitroprusside /milrinone = long term unloading
of LV and repeat testing after 6 weeks of milrinone, LV assist
device placement
 Reduction in PAWP but the PVR remains >4 suggesting some
out of proportion pulmonary vascular disease– it is recommend
testing with 100% O2 and iNO after the nitroprusside/milrinone
study

47. Conclusion
 Vasodilatory testing for PAH is an evidence-based practice that aims to
predict patients who might respond to calcium channel blockers
 Vasodilatory testing is recommended in patients with IPAH, HPAH,
DPAH
 The ACC and ECC guidelines have recommended iNO as the agent of
choice for vasodilatory testing, with intravenous epoprostenol or
intravenous adenosine as reasonable alternatives
 More research is needed in the future to evaluate further the utility of
other testing agents and to measure how accurately they predict the
response to CCBs

48. Thank you